Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate

Abstract

An inexorable decline in maximum heart rate (mHR) progressively limits human aerobic capacity with advancing age. This decrease in mHR results from an age-dependent reduction in "intrinsic heart rate" (iHR), which is measured during autonomic blockade. The reduced iHR indicates, by definition, that pacemaker function of the sinoatrial node is compromised during aging. However, little is known about the properties of pacemaker myocytes in the aged sinoatrial node. Here, we show that depressed excitability of individual sinoatrial node myocytes (SAMs) contributes to reductions in heart rate with advancing age. We found that age-dependent declines in mHR and iHR in ECG recordings from mice were paralleled by declines in spontaneous action potential (AP) firing rates (FRs) in patch-clamp recordings from acutely isolated SAMs. The slower FR of aged SAMs resulted from changes in the AP waveform that were limited to hyperpolarization of the maximum diastolic potential and slowing of the early part of the diastolic depolarization. These AP waveform changes were associated with cellular hypertrophy, reduced current densities for L- and T-type Ca(2+) currents and the "funny current" (If), and a hyperpolarizing shift in the voltage dependence of If. The age-dependent reduction in sinoatrial node function was not associated with changes in β-adrenergic responsiveness, which was preserved during aging for heart rate, SAM FR, L- and T-type Ca(2+) currents, and If. Our results indicate that depressed excitability of individual SAMs due to altered ion channel activity contributes to the decline in mHR, and thus aerobic capacity, during normal aging.

Fig. 1.

Parallel age-dependent declines in HR and SAM AP FR. (A) Representative ECG recordings of iHRs and mHRs from mice aged 2–3 mo (black), 21–24 mo (green), and 32+ mo (red). (Scale bar: 250 ms.) (B) iHRs (filled circles) and mHRs (open circles) from mice of the three age groups. (C) Representative APs recorded from acutely dissociated SAMs from mice of different ages. (Scale bars: 250 ms, 70 mV). (D) iHR (filled circles) and mHR (open circles) AP FRs from SAMs isolated from mice of different ages. The lines in B and D are linear regressions to the data.

Fig. 2.

Slower AP FRs in aged SAMs result from limited changes in the sinoatrial AP waveform. (A) Representative APs recorded from SAMs in mice aged 2–3 mo (black), 21–24 mo (green), and 32+ mo (red) superimposed at time of peak. Dashed lines indicate the slopes of the DD, and arrowheads mark the MDP. (B) Average (±SEM) MDP and early DD rate (eDDR) in SAMs from mice of different ages. *P < 0.05, one-way ANOVA with a Holm–Sidak posttest.

Fig. 3.

Decreased I_Ca,L and I_Ca,T conductance densities in aged SAMs. (A and B) Average (±SEM) current-voltage relationships and representative currents for I_Ca,L and I_Ca,T in SAMs in mice aged 2–3 mo (black), 21–24 mo (green), and 28 mo (red) in the absence (filled circles) and presence (open circles) of 1 μM ISO. (Scale bars: 5 pA/pF, 25 ms.) (Insets) Representative current families. (C and D) Average (±SEM) peak I_Ca,L and I_Ca,T densities in SAMs in mice aged 2–3 mo (black), 21–24 mo (green), and 28 mo (red) in the absence (filled bars) and presence (hatched bars) of ISO. *P < 0.05, one-way ANOVA with a Holm–Sidak posttest.

Fig. 4.

Hyperpolarized activation midpoint for I_f in aged SAMs. (A) Normalized average (±SEM) conductance-voltage relationships for I_f in SAMs in mice aged 2–3 mo (black), 21–24 mo (green), and 32+ mo (red) in the absence (filled circles) and presence (open circles) of 1 μM ISO. (Insets) Representative I_f current families normalized to cellular capacitance. (Scale bars: 15 pA/pF, 750 ms.) (B) Average (±SEM) V_1/2 values for I_f in isolated SAMs from mice of different ages in the absence (filled bars) or presence (hatched bars) of ISO. *P < 0.05, one-way ANOVA with a Holm–Sidak posttest.